|
The proposed research will test an innovative strategy to make kidney tissue resistant to oxygen deprivation (hypoxia), a phenomenon that occurs during transplantation procedures and upon acute kidney injury (AKI). This strategy is inspired by our preliminary data on the discovery of rhodoquinone (RQ), a novel mammalian metabolite that is present in the kidney and serves as an electron carrier for the mitochondrial electron transport chain (ETC). In textbook portrayals, the mammalian ETC serves metabolic pathways by transporting electrons from complexes I and II, via the electron carrier ubiquinone (UQ), to the terminal electron acceptor oxygen (O2). Our preliminary data reveal that RQ delivers electrons to fumarate, instead of oxygen, establishing for the first time that mammalian tissues can employ distinct ETC pathways. The proposed research will leverage this knowledge of flexibility in the ETC to divert electron flow more efficiently through the RQ circuit as a strategy to protect kidney tissue from ischemia-induced AKI. Central to this strategy is a custom-synthesized and first-in-class small molecule capable of reprogramming the ETC from the UQ to the RQ-directed circuit. Using this novel tool, the proposed research will first address the metabolic impacts of reprograming the ETC in healthy and ischemic kidney tissue. Then, we will assess how reprogramming the ETC impacts reperfusion efficiency and renal function upon ischemia-induced AKI. Beyond shedding light on the fundamental role of distinct ETC circuits in renal metabolism, this work will determine if the RQ-directed ETC circuit can be exploited to make kidney tissue resistant to hypoxia. Although the proposed aims are extremely risky, as this strategy has never been tested before, if successful, this work will unequivocally transform the field by opening the doors to both fundamental studies on metabolic flexibility in the ETC of kidney tissue and translational studies on clinical development of molecules that reprogram the ETC to mitigate ischemic injury. Finally, if our hypothesis is correct, reprogramming the ETC could significantly extend the lifetime of organs post-mortem, paving a clear path forward for the development of a centralized organ bank that is readily accessible for transplant patients.
|